Chronic alcohol exposure is known to cause resistance to ethanol-induced membrane disordering measured in vitro, usually referred to as membrane tolerance. Initial studies on the phospholipid acyl chain dependence of the effects of alcohol demonstrate that polyunsaturated acyl chains potentiate the effect of alcohol. This finding, coupled with the observation made in this Laboratory that alcohol depletes the long-chain polyunsaturated fatty acids, such as 20:4n6 and 22:6n3, may provide an explanation for the development of the tolerance effect. A novel model for phospholipid acyl chain packing, developed in this Laboratory, includes the formation of lateral domains, which is driven by the strong interactions of the saturated sn-1 chains relative to the polyunaturated sn-2 chains. This model is supported by our findings that mixtures of disaturated PCs and a dipolyunsaturated (di22:6n3) PC show lateral phase separation in the gel phase. Phase transition studies of a variety of mixed-chain phosphatidylethanolamines (PE) demonstrate that this class of phospholipids can undergo a liquid crystalline to hexagonal II phase transition in the physiological temperature range and may in this way provide unique structural features to the membranes in which they reside.